Nipocalimab is a human IgG1 monoclonal antibody specifically targeting the IgG Fc binding site of FcRn with high specificity and high affinity at both neutral (extracellular) and acidic pH (intracellular) resulting in the reduction of circulating IgG, including IgG autoantibodies, without affecting other immunoglobulins (IgA, IgE or IgM). Nipocalimab did not demonstrate any clinically relevant impact on circulating levels of albumin, which binds at a different site on FcRn.
IgG autoantibodies are the underlying cause of the pathogenesis of MG. IgG autoantibodies impair neuromuscular transmission by binding to AChR, MuSK or LRP4.
Nipocalimab reduces the placental transfer of IgG from mother to foetus.
In a double-blind placebo-controlled study in gMG patients, intravenous administration of nipocalimab at the recommended dose regimen resulted in a significant rapid reduction in total IgG serum concentrations of 75% compared to baseline within 2 weeks of treatment initiation, followed by a sustained reduction of approximately 70% compared to baseline from Week 4 through to Week 24. Similar dose-dependent reductions in all IgG subclasses (IgG1, IgG2, IgG3, and IgG4) were observed.
The mean (SD) volume of distribution is 2.84 (0.63) L or 0.0359 (0.0087) L/kg.
Nipocalimab is expected to be degraded by proteolytic enzymes into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Nipocalimab exhibits concentration-dependent pharmacokinetics. Following a single intravenous administration of 15 mg/kg of nipocalimab, the mean clearance is 0.0627 L/h and half-life is 29.3 hours. After stopping administration, serum IgG concentrations recover towards baseline levels within approximately 8 weeks.
Nipocalimab exhibits non-linear, dose-dependent pharmacokinetics. Following a single intravenous infusion of nipocalimab at doses ranging from 0.3 to 60 mg/kg in healthy participants, Cmax increased in a dose-proportional manner while AUC increased in a greater than dose proportional manner.
Due to the relatively short half-life of nipocalimab, repeated dosing administered in accordance with the recommended maintenance dose results in no drug accumulation over time.
Pharmacokinetics of nipocalimab were evaluated in adolescent patients 12 to 17 years of age with gMG (n=8). Following treatment with nipocalimab at the recommended dose regimen, the observed serum nipocalimab concentrations were comparable between adult and adolescent patients with gMG (table).
Serum nipocalimab concentrations in adult and adolescent patients with gMG:
| Timepoint | Exposure Parameter | Adolescents (n=8) Median (IQ Range) | Adults (n=97) Median (IQ Range) |
|---|---|---|---|
| Initial dose | Ceoi,ld (μg/mL) | 701 (673, 922) | 864 (774, 1000) |
| Ctrough,ld (μg/mL) | 0.01 (BQL, 0.02) | 0.02 (BQL, 0.03) | |
| Maintenance doses | Ceoi,ss (μg/mL) | 394 (335, 491) | 424 (392, 479) |
| Ctrough,ss (μg/mL) | BQL | BQL |
BQL = Below Quantification Limit (i.e., <0.01 μg/mL); Ceoi,ld = end of infusion concentration after 30 mg/kg initial dose; Ctrough,ld = pre-dose concentration at Week 2 after 30 mg/kg initial dose; Ceoi,ss = end of infusion concentrations at steady state after 15 mg/kg every two weeks maintenance doses; Ctrough,ss = pre-dose concentration at steady state after 15 mg/kg every two weeks maintenance doses; IQ = interquartile.
Clinical studies with nipocalimab did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger adult patients. No apparent differences in clearance and volume of distribution were observed in patients ≥65 years of age compared to patients <65 years of age, suggesting no dose adjustment is needed for elderly patients.
A population pharmacokinetics analysis assessing the effects of age, sex, and race did not suggest any clinically relevant impact of these covariates on nipocalimab exposures.
Body weight has an impact on systemic exposure to nipocalimab. The recommended weight-based dosing (in mg/kg) accounts for the differences in patient body weight.
No formal studies have been performed in patients with renal impairment. Renal impairment is not expected to affect the pharmacokinetics of nipocalimab. Based on a population pharmacokinetic analysis, which included patients with mild to moderate renal impairment, renal function had no clinically relevant effect on nipocalimab apparent clearance. No dose adjustment is required in patients with renal impairment.
No formal studies have been performed in patients with hepatic impairment. Nipocalimab is not metabolised by cytochrome P450 enzymes, and therefore, hepatic impairment is not expected to affect the pharmacokinetics of nipocalimab. Based on a population pharmacokinetic analysis, which included participants with mild and a limited number of participants with moderate hepatic impairment, there was no clinically relevant effect on nipocalimab apparent clearance. No dose adjustment is required in patients with hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
There were no nipocalimab-related adverse effects on male and female fertility in non-pregnant cynomolgus monkeys in a 6-month repeat-dose study when evaluated by changes in the reproductive organs (organ weights and histopathology). All females and 80% of males, at the highest dose tested, became sexually mature during the 6-month treatment period in which exposure levels up to 44 times the expected exposure level in patients on the recommended maintenance dose were evaluated.
In an enhanced pre- and postnatal development study, where pregnant cynomolgus monkeys were intravenously exposed to nipocalimab during the late first, second and third trimesters of pregnancy, 16% (4/25) of placentas showed large, central placental infarctions and thrombosis of maternal spiral arteries. Three of the 4 cases of placental infarction were associated with second or third trimester foetal losses. The placental infarctions may be related to maternal immunogenicity in pregnant cynomolgus monkeys. The clinical relevance of these findings is unknown. Nipocalimab exposure levels (AUC) in pregnant cynomolgus monkeys reached at least 5 to 24 times the expected exposure level in non-pregnant women based on the recommended maintenance dose regimen. No pre- or postnatal development concerns were raised. Foetuses and infants from treated dams showed negligible exposure to maternal nipocalimab but had low levels of IgG at birth. The infant IgG levels recovered within 6 months. There was no adverse impact on immune function of the infants of treated dams as assessed by a T-cell Dependent Antibody Response assay.
The mutagenic potential of nipocalimab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with nipocalimab.
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